Human Liver Stem Cells: A Liver-Derived Mesenchymal Stromal Cell-Like Population With Pro-regenerative Properties.

Stefania Bruno,Marta Tapparo,Giovanni Camussi,Giulia Chiabotto,Chiara Pasquino,Victor Navarro-Tableros,Valentina Fonsato,Maria Beatriz Herrera Sanchez

doi:10.3389/fcell.2021.644088

Stefania Bruno, Marta Tapparo + Show 6 more

Open Access

https://doi.org/10.3389/fcell.2021.644088

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Abstract

Human liver stem cells (HLSCs) were described for the first time in 2006 as a new stem cell population derived from healthy human livers. Like mesenchymal stromal cells, HLSCs exhibit multipotent and immunomodulatory properties. HLSCs can differentiate into several lineages under defined in vitro conditions, such as mature hepatocytes, osteocytes, endothelial cells, and islet-like cell organoids. Over the years, HLSCs have been shown to contribute to tissue repair and regeneration in different in vivo models, leading to more than five granted patents and over 15 peer reviewed scientific articles elucidating their potential therapeutic role in various experimental pathologies. In addition, HLSCs have recently completed a Phase 1 study evaluating their safety post intrahepatic injection in infants with inherited neonatal onset hyperammonemia. Even though a lot of progress has been made in understanding HLSCs over the past years, some important questions regarding the mechanisms of action remain to be elucidated. Among the mechanisms of interaction of HLSCs with their environment, a paracrine interface has emerged involving extracellular vesicles (EVs) as vehicles for transferring active biological materials. In our group, the EVs derived from HLSCs have been studied in vitro as well as in vivo. Our attention has mainly been focused on understanding the in vivo ability of HLSC–derived EVs as modulators of tissue regeneration, inflammation, fibrosis, and tumor growth. This review article aims to discuss in detail the role of HLSCs and HLSC-EVs in these processes and their possible future therapeutic applications.

Highlights

At present, it is estimated that 1.5 billion people are affected by chronic liver diseases that eventually progresses into fibrosis and cirrhosis (Moon et al, 2020)
Cell therapy is an alternative form of treatment for liver disease that involves in vitro amplification followed by transplantation of healthy stem/progenitor cells into patients, ideally through a minimally invasive procedure (Wei et al, 2020)
Several issues need to be taken into consideration in order to obtain this goal: firstly, it is essential that the cells remain genetically stable and non-tumorigenic as they proliferate; secondly, a sufficient number of healthy cells is required and thirdly, the cells need to maintain their properties under storage conditions

Summary

Introduction

It is estimated that 1.5 billion people are affected by chronic liver diseases that eventually progresses into fibrosis and cirrhosis (Moon et al, 2020). Transplanting of hepatocytes, obtained from adult or neonatal livers, is considered to be an alternative therapy to organ transplantation, and represents a potential treatment option in patients with acute liver failure (Dhawan et al, 2010), a major limitation is the availability of organs for hepatocytes isolation as well as the difficulty to expand them in vitro (Squires et al, 2017) In this contest, the use of stem cells as a possible source of cells for hepatic reconstitution has emerged as a new potential therapeutic approach. Human liver stem cells (HLSCs) were isolated for the first time in 2006, using a unique method based on stringent conditions of culture, whereby mature hepatocytes undergo cell death leaving clones of HLSCs that are expandable and exhibit multiple differentiating capabilities (Herrera et al, 2006). This discovery was considered to be innovative, leading to a patent approval in 2006 as a novel source of hepatic stem cells (WO2006126219A1, Liver progenitor cells)

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